1. Field of the Invention
This invention relates to dibenzofurancarboxamidetype compounds which exhibit 5HT.sub.3 -antagonist properties including unique CNS, anti-emetic and gastric prokinetic activity and which are void of any significant D.sub.2 receptor binding affinity. This invention relates also to stereospecific processes for the preparation, separation and purification of said compounds.
5-Hydroxytryptamine, abbreviated "5-HT", is commonly known as serotonin. Serotonin is found throughout the body including the gastrointestinal tract, platelets, spleen and brain, appears to be involved in a great number of physiological processes such as neurotransmission at certain neurones in the brain, and is implicated in a number of central nervous system (CNS) disorders. Additionally, serotonin appears to act as a local hormone in the periphery; it is released in the gastrointestinal tract, where it increases small intestinal motility, inhibits stomach and colon motility, and stimulates stomach acid production. Serotonin is most likely involved in normal intestinal peristalsis.
The various physiological activities exerted by serotonin are related to the variety of different receptors found on the surface membrane of cells in different body tissue. The first classification of serotonin receptors included two pharmacologically distinct receptors discovered in the guinea pig ileum. The "D" receptor mediates smooth muscle contraction and the "M" receptor involves the depolarization of cholinergic nerves and release of acetylcholine. Three different groups of serotonin receptors have been identified and the following assignment of receptors has been proposed: D-receptors are 5-HT.sub.2 -receptors; M-receptors are termed 5-HT.sub.3 -receptors; and all other receptors, which are clearly not 5-HT.sub.2 or 5-HT.sub.3, have been referred to as 5-HT.sub.1 -like and work is being continued on this classification.
5-HT.sub.3 -receptors have been located in non-neurological tissue, brain tissue, and a number of peripheral tissues related to different responses. It has been reported that 5-HT.sub.3 -receptors are located on peripheral neurones where they are related to serotonin's (excitatory) depolarizing action. The following subtypes of 5-HT.sub.3 -receptor activity have been reported: action involving postganglionic sympathetic and parasympathetic neurones, leading to depolarization and release of noradrenaline and acetylcholine, respectively (5-HT.sub.38 subtype); action on enteric neurones, where serotonin may modulate the level of acetylcholine (5-HT.sub.3C subtype); and action on sensory nerves such as those involved in the stimulation of heart nerve endings to produce a reflex bradycardia (5-HT.sub.3A subtype), and also in the perception of pain.
Highly selective 5-HT.sub.3 -antagonists have been shown to be very effective at controlling and preventing emesis (vomiting) induced by chemotherapy and radiotherapy in cancer patients. The anti-emetic effects of 5-HT.sub.3 -antagonists in animals exposed to cancer chemotherapy or radiation are similar to those seen following abdominal vagotomy. The antagonist compounds are believed to act by blocking 5-HT.sub.3 -receptors situated on the cell membranes of the tissue forming the vagal afferent input to the emetic coordinating areas on the brain stem.
Serotonin is also believed to be involved in the disorder known as migraine headache. Serotonin released locally within the blood vessels of the head is believed to interact with elements of the perivascular neural plexus of which the afferent, substance P-containing fibers of the trigeminal system are believed relevant to the condition. By activating specific sites on sensory neuronal terminals, serotonin is believed to generate pain directly and also indirectly by enhancing the nociceptive effects of other inflammatory mediators, for example bradykinin. A further consequence of stimulating the afferent neurones would be the local release of substance P and possibly other sensory mediators, either directly or through an axon reflex mechanism, thus providing a further contribution to the vascular changes and pain of migraine. Serotonin is known to cause pain when applied to the exposed blister base or after an intradermal injection; and it also greatly enhances the pain response to bradykinin. In both cases, the pain message is believed to involve specific 5-HT.sub.3 -receptors on the primary afferent neurones.
5-HT.sub.3 -antagonists are also reported to exert potential antipsychotic effects, and are believed to be involved in anxiety. Although not understood well, the effect is believed to be related to the indirect blocking of serotonin 5-HT.sub.3 -mediated modulation of dopamine activity.
Many workers are investigating various compounds having 5-HT.sub.3 -antagonist activity.
The development of 5-HT.sub.3 agents originated from work carried out with metoclopramide (Beecham's Maxolon, A.H. Robins' Reglan), which is marketed for use in the treatment of nausea and vomiting at high doses. Metoclopramide is a dopamine antagonist with weak 5-HT.sub.3 -antagonist activity, which becomes more prominent at higher doses. It is reported that the 5-HT.sub.3 activity and not the dopamine antagonism is primarily responsible for its anti-emetic properties. Other workers are investigating this compound in connection with the pain and vomiting accompanying migraine.
Merrell Dow's compound MDL-72222 is reported to be effective as an acute therapy for migraine, but toxicity problems have reportedly ended work on this compound. Currently four compounds, A.H. Robins' Zacopride, Beecham's BRL-43694, Glaxo's GR-38032F and Sandoz' ICS-205-930 are in clinical trials for use in chemotherapyinduced nausea and vomiting. GR-38032F is also in clinical trials in anxiety and schizophrenia, and reportedly, Zacopride in anxiety, while ICS-205-930 has been shown to be useful in treating carcinoid syndrome.
Compounds reported as gastroprokinetic agents include Beecham's BRL-24924, which is a serotonin-active agent for use in gut motility disorders such as gastric paresis, audition reflux esophagitis, and is known to have also 5-HT.sub.3 -antagonist activity.
Metoclopramide, Zacopride, Cisapride and BRL-24924 are characterized by a carboxamide moiety situated para to the amino group of 2-chloro-4-methoxy aniline. BRL-43694, ICS-205-930, GR-38032F and GR-65630 are characterized by a carbonyl group in the 3-position of indole or N-methyl indole. MDL-72222 is a bridged azabicyclic 3,5-dichlorobenzoate, while Zacopride, BRL-24924, BRL-43694 and ICS-205,930 have also bridged azabicyclic groups in the form of a carboxamide or carboxylic ester.
Bicyclic oxygen containing carboxamide compounds wherein the carboxamide is ortho to the cyclic oxygen moiety are reported to have antiemetic and antipsychotic properties in EPO Publ. No. 0234872.
Dibenzofurancarboxamides and 2-carboxamide-substituted benzoxepines are reported to have 5-HT.sub.3 -antagonist and gastroprokinetic activity in U.S. Pat. Nos. 4,859,683, 4,857,517, 4,924,010 and 4,863,921, all of which are assigned to the same assignee as the present application.
Among the reported compounds are stereoisomers which are synthesized by using chiral synthesis, i.e., asymmetric induction methods of synthesis.
2. Reported Developments
Speaking generally, synthesis with asymmetric induction have been known in the prior art. A synthesis with asymmetric induction is commonly defined as a process in which a chiral unit in an ensemble of substrate molecules induces, by a reaction with achiral units, resulting molecules in such a manner that the stereoisomeric products are produced in unequal amounts. Such an asymmetric syntheses may be of great economic value for excluding or reducing the amount of unwanted isomers when only one of the diastereomers is of use or interest.
The reactants used in an asymmetric synthesis can be at least one chiral component consisting of a chemical reagent, solvent or catalyst. Alternatively, by selection of specific enantiomers as starting compounds, the preferred stereoisomer in a predominant amount can be induced. However, selection of enantiomerically pure intermediates does not always result in a stereoselective synthesis since chirality of an intermediate could be lost due to racemization under one or more sets of reaction conditions. Consequently, synthetic processes typically involve extra reaction steps to accomplish the stereoselective result as well as involve a tedious recrystallization step.
In co-pending application Ser. No. 351,625, the synthesis of the dibenzofurancarboxamides proceeds via condensation of a substituted dibenzofuran-4-carboxylic acid or a 6,7,8,9-tetrahydrodibenzofuran-carboxylic acid or a 5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid or their acid halides or esters with an amine of the formula H.sub.2 N-R which results in the corresponding carboxamide. The process terminates with a recrystallization step in a relatively poor overall yield. This synthesis is made difficult by the presence of an acid sensitive chiral center which racemizes under mild acid conditions. The present invention is based on a discovery that acid sensitive intermediates can be used in a stereoselective synthesis using conditions which do not affect the product's chiral centers. Using the present invention, yields which are an order of magnitude greater than previously achieved are obtainable with about 95% to about 99% chiral purity.